The abuse of, and addiction to, d-methamphetamine (METH) interferes with many aspects of personal health, vocational performance, interpersonal relationships and financial well being. Behavioral consequences of METH abuse and the METH trade also strain legal and emergency medical resources throughout the US. METH is therefore a growing public health concern. Current therapeutic approaches for METH addiction are less than completely effective and no approved pharmacotherapies for METH addiction exist. Recent successes in early clinical trials using immunotherapeutic approaches for cocaine and nicotine addiction have motivated interest in creating similar approaches for methamphetamine addiction. The studies proposed will create candidate active vaccines specific for METH (MCV) and evaluate the most promising candidates in a cascade of in vivo models. Constrained METH haptens will be synthesized to create approximately six MCV candidates. MCVs will be evaluated for the generation of suitable antibody titer with specific METH activity in mice and rats. Pilot studies in rhesus macaque monkeys will also be undertaken to determine optimal parameters for generating high antibody titers in this species. A subset of the most effective MCVs will then be evaluated in rats to determine the potential for altering METH pharmacokinetics in vivo. The top MCV candidate will then be similarly evaluated for pharmacokinetic activity in monkeys. It is hypothesized that effective immunization will result in sequestration of METH in the periphery and a lowering of METH levels in brain. Further studies will determine if the MCV immunization can modify cardiac, hyperthermic and hyperlocomotor responses to METH challenge in rats and monkeys using a radiotelemetric system. Finally, it will be determined if MCV immunization can attenuate the reinforcing properties of METH using a rat intravenous self-administration procedure.